Combo Products Won't Get Special Review Pathway At US FDA Anytime Soon

The US FDA appears to have shifted away from consideration of a specific review pathway for combination products and is instead focusing on implementing the provisions on the topic from the 21^st Century Cures Act as well as making other administrative changes to smooth evaluation of the products.

Testifying before the Senate HELP Committee at a March 21 hearing on user fees, Center for Devices and Radiological Health (CDRH) Director Jeffrey Shuren noted that while FDA is "always open to other ideas to make the program work better," it is more concerned right now with putting the recently enacted law in place at the agency.

Center for Drug Evaluation and Research Director (CDER) Janet Woodcock concurred with Shuren.

The comments came in response to a question from Sen. Sheldon Whitehouse, D-R.I., who asked the witnesses whether they feel the need for Congress to establish a third pathway for combination products.

"As long as there is no pressure for [Congress] to develop a third way right now, if [FDA] would rather work through [implementing the Cures legislation first], I think that is our understanding," Whitehouse said.

Committee Chairman Sen. Lamar Alexander, R-Tenn., agreed, noting that "being able to let you work through the best ways to do it before we jump to different pathway might be the more practical approach."

Currently, the Office of Combination Products assigns products to a specific lead review center based on the primary mode of action. Sponsors can inquire from FDA about how their product will be regulated through a formal, binding Request for Designation (RFD), or a more flexible, informal Pre-Request for Designation (Pre-RFD). (Also see "Combo Product Consultations At US FDA May Suffer As They Become Formalized" - Pink Sheet, 13 Jan, 2017.)

The 21st Century Cures Act contains provisions for reforming FDA's oversight of combination products. For one, it instructs that the agency be wary about designating a combo-product as a drug versus a device. (Also see "Combo Product Review Pilot At US FDA Will Offer All Applications Intercenter Consults" - Pink Sheet, 20 Dec, 2016.)

The agency generally has a bias toward assigning products to be regulated by CDER, which has become a point of contention, as device-regulated products have a less demanding regulatory pathway. (Also see "Combination Product Designations At US FDA Need Faster Appeals, Petition Says" - Pink Sheet, 9 Mar, 2017.)

"In determining the primary mode of action of a combination product, the Secretary shall not determine that the primary mode of action is that of a drug or biological product solely because the combination product has any chemical action within or on the human body," the Cures Act states.

The Cures legislation also establishes mandatory meetings between FDA and combination product developers and clarifies the process for resolving disputes between FDA product centers. (Also see "The Evolution Of 21^st Century Cures Legislation" - Pink Sheet, 29 Nov, 2016.)

A Shift From Prior Thinking

In June 2015, Shuren said that it may be time to consider a new pathway for combination products as a result of companies and FDA having frustrations with mismatches between drug and device regulations and with communication challenges between the product centers that lead to inefficiencies.

Shuren didn't offer specifics on what such a pathway might look like during his talk at the annual Drug Innovation Association conference, but said he was floating the idea to start a conversation. (Also see "Will Combination Products Join The User Fee Family?" - Pink Sheet, 29 Jun, 2015.)

Former FDA Commissioner Robert Califf also expressed support for a third pathway for combination products during his confirmation hearing in November of 2015. He said that the existing framework for combination products was not suitable, and that it is "a strong view at the FDA that we need another pathway that will give the FDA the flexibility to require the data that’s needed to assure the public that the proposed treatment is safe and effective." (Also see "Califf Supports Combo Products Pathway At Confirmation Hearing" - Pink Sheet, 17 Nov, 2015.)

Shuren Touts Improvements

Although FDA’s problems of reviewing combination products have been well-known – including a lack of user fee goals and deadline coordination between review centers and inefficiencies with intercenter consultations – Shuren did point out that the agency has made some recent improvements in the area.

He touted the creation of the cross-center Combination Product Policy Council, which has "been putting policies in place to help have much more coordinated activity."

"For example, the agency has already modified how we consult various centers," Shuren said. "We have time frames. … The early data on it is showing that it is helping."

The agency is also aiming to have its intercenter consult request (ICCR) process fully implemented by mid-2017, when it will apply to all combination product submissions. The pilot was initially launched in August 2016, and has the goal of facilitating "timely, appropriately tailored and well-informed submission review." (Also see "Combo Product Review Pilot At US FDA Will Offer All Applications Intercenter Consults" - Pink Sheet, 20 Dec, 2016.)

Sponsors, however, have still clamored for the agency to implement firm timelines for appeals of designation decisions. A recent citizen petition specifically requests that FDA amend 21 C.F.R. § 3.8 so that the agency will have a deadline of 60 days following the submission of an appeal to complete its review of an appeal. (Also see "Combination Product Designations At US FDA Need Faster Appeals, Petition Says" - Pink Sheet, 9 Mar, 2017.)